Frequency Therapeutics — Hearing Loss Regeneration

[GlennS]

Is it even possible to release a drug when it's going through phase 3? I thought this wasn't possible. I thought phase 3 was needed to be passed before commercialisation.
You know even when hundreds have been tested with FX-322 it still needs to be tested on thousands more.

Corona vaccines aren't following standard procedures. Of course, that's a special circumstance. I doubt the powers that be would see this as urgent enough to do that.

 

[FGG]

Corona vaccines aren't following standard procedures. Of course, that's a special circumstance. I doubt the powers that be would see this as urgent enough to do that.

A lot of cancer drugs have also skipped phase 3. The results have to be very compelling and for an unmet need for this to generally happen.

 

[BBakkers]

Corona vaccines aren't following standard procedures. Of course, that's a special circumstance. I doubt the powers that be would see this as urgent enough to do that.

Agree, but if you don't try you'll never know. I think if more people try to access it early on there could be a chance. Nothing ventured, nothing gained.

 

[all to gain]

A lot of cancer drugs have also skipped phase 3. The results have to be very compelling and for an unmet need for this to generally happen.

I'm frothing at the mouth to get this stuff. And we all know many others are, too.

Did you ever send that letter to the FDA?

 

[FGG]

I'm frothing at the mouth to get this stuff. And we all know many others are, too.

Did you ever send that letter to the FDA?

No. It doesn't make sense to during COVID-19. But I'm re-thinking how important it is anyway. Because I really do think compassionate/expanded use will be much earlier access regardless of what the FDA does. The only difference getting it after approval might mean insurance covers it.

 

[Lola808]

Had an interesting experience yesterday. Went to a hearing aid specialist to see what he might let me try. More of a sales man than compassionate.

I asked him to look up FX-322 and his response was "this would put me out of business". He collects about $200 a month for 5 years from his patients and renews them.

These are the people who keep these studies from advancing.

 

[Lucifer]

A lot of cancer drugs have also skipped phase 3. The results have to be very compelling and for an unmet need for this to generally happen.

I think FX-322 has a good chance of getting very compelling results, hopefully they open expanded access soon.

 

[FGG]

I think FX-322 has a good chance of getting very compelling results, hopefully they open expanded access soon.

Unlike FDA approval, Expanded Use technically does not depend on results. They could do it now if they wanted to (as long as they had an idea what the proper dosing might look like) but haven't scaled up production to meet the inevitable massive demand. They have said this on their website that they are not granting any compassionate use requests until further testing is complete (likely to get dosing right esp) and until they could meet demand.

My guess is the earliest indicator would be when they build a dedicated production line or if Astellas devoted part of their supply line to making FX-322 in mass.

Tl;dr: The FDA needs compelling results to advance trials and approve drugs but until then, Frequency could still offer the drug at any point if a doctor applied for compassionate use. However, Frequency has explicitly said they are not ready to grant any of those requests for the time being.

 

[Lucifer]

Unlike FDA approval, Expanded Use technically does not depend on results. They could do it now if they wanted to (as long as they had an idea what the proper dosing might look like) but haven't scaled up production to meet the inevitable massive demand. They have said this on their website that they are not granting any compassionate use requests until further testing is complete (likely to get dosing right esp) and until they could meet demand.

My guess is the earliest indicator would be when they build a dedicated production line or if Astellas devoted part of their supply line to making FX-322 in mass.

Tl;dr: The FDA needs compelling results to advance trials and approve drugs but until then, Frequency could still offer the drug at any point if a doctor applied for compassionate use. However, Frequency has explicitly said they are not ready to grant any of those requests for the time being.

I didn't realise they could have open expanded use at anytime. I thought they had to at least complete Phase 2 before it could happen since they don't know what is the safe and efficient dose.

 

[FGG]

I didn't realise they could have open expanded use at anytime. I thought they had to at least complete Phase 2 before it could happen since they don't know what is the safe and efficient dose.

The only requirement is that it has been previously tested in humans (e.g. Phase 1). You don't have to have the exact dosing worked out because you and your doctor are petitioning to try a drug where all of that has not been fully worked out (which is what the 3 phases are designed to do) in the name of "the right to try" something in an otherwise desperate situation.

It's Frequency who have said that they would rather wait and find out more as well as scale up production. It is completely up to a company to decide when and if they use compassionate use. I do agree with them that there is literally no way they are set up to supply (at this time) for the kind of crazy demand they would have.

 

[AtlasFainted]

For those worried about drug delivery to the low frequencies, there is a new surgical approach called canalostomy. Unlike Novartis' surgical approach for their drug which significantly damages the cochlea (cochleastomy), this doesn't at all as it enters through the edge of the vestibular system and apparently only causes minor, temporary damage to that system (none to the hearing system).

Seems like something that could be done without any additional trials if an otological surgeon wanted to do this off label.

Here is one paper on the procedure but there are a few.

https://www.jove.com/video/57351/canalostomy-as-surgical-approach-to-local-drug-delivery-into-inner

This type of surgery was also mentioned in one of Chen's papers for viral vectored gene delivery and what's neat is it starts from Apex to Base and can use the natural fluid movement of the cochlea (in the perilymph) for the drug to flow to the whole cochlea evenly since you are going "with the current". If the drug needs to be injected into the endolymph because it was only tested in that environment, that can be accessed from this site, too.

So low frequency sufferers with hair cell damage up to the moderately severe hearing loss range (possibly with severe too as long as you still have enough support cells) might have something they can discuss with an Otologic surgeon if they truly can't wait for FX-322 2.0 with better diffusion (for some people it is literally life or death). It definitely might be worth inquiring about for the severe sufferers.

This is really interesting. Any idea on how this procedure is actually done? Is it an injection or something more complicated?

The link you gave requires an 'institutional email address' but I don't have one. I also did some Googling but mainly get back results for animal testing. Not much look searching for videos either... It must be a pretty new procedure indeed!

I'm not sure if it would be worth the trouble for me to consider or not. I'd ideally like to get all my problems fixed ASAP & not incrementally. I have high frequency tinnitus in both ears and also some noticeable hearing loss (seems like it affects lower frequencies as well) in my right ear.

I also saw you mention that support cells might not be present where there is total deafness. Is this true for noise-induced hearing loss as well? I have almost no hearing above 9kHz in my right ear...

 

[Lucifer]

The only requirement is that it has been previously tested in humans (e.g. Phase 1). You don't have to have the exact dosing worked out because you and your doctor are petitioning to try a drug where all of that has not been fully worked out (which is what the 3 phases are designed to do) in the name of "the right to try" something in an otherwise desperate situation.

It's Frequency who have said that they would rather wait and find out more as well as scale up production. It is completely up to a company to decide when and if they use compassionate use. I do agree with them that there is literally no way they are set up to supply (at this time) for the kind of crazy demand they would have.

Thanks @FGG. I hope they offer compassionate use after Phase 2a is done.

 

[Lucifer]

I know in Phase 1B they tested that even up to 90 days it showed more signs of improvement compared to Days 30 and 60.

Have they tested if the benefits last more than 90 days?

 

[FGG]

This is really interesting. Any idea on how this procedure is actually done? Is it an injection or something more complicated?

The link you gave requires an 'institutional email address' but I don't have one. I also did some Googling but mainly get back results for animal testing. Not much look searching for videos either... It must be a pretty new procedure indeed!

I'm not sure if it would be worth the trouble for me to consider or not. I'd ideally like to get all my problems fixed ASAP & not incrementally. I have high frequency tinnitus in both ears and also some noticeable hearing loss (seems like it affects lower frequencies as well) in my right ear.

I also saw you mention that support cells might not be present where there is total deafness. Is this true for noise-induced hearing loss as well? I have almost no hearing above 9kHz in my right ear...

Yes, very new and extremely promising.

It's a surgical procedure to get to the edge of the semi circular canal where the injection is given. I'm not sure if it has yet been tried on humans but Chen has mentioned using that approach for his drugs in one of his papers. It's apparently a technically "easier" surgery with much less risk than the cochleastomy that's already done. I haven't seen any paper mention any anatomic difference that would prevent this in humans. The fact that hearing regeneration researchers are looking into this (there has been an uptick in papers on this) tells me it's being seriously looked into.

If you truly have profound hearing loss you will eventually get "flat epithelial" in that location which is devoid of all IHC, OHC and SCs. I spoke to a "flat epithelial/profound hearing loss" researcher and this what she said:

"Profound hearing loss in an audiogram suggests that you have no sensory HCs or supporting cells or auditory nerves in these regions."

She said many studies, including her own have confirmed this. She did feel optimistic, though, that in 15-20 years there would be a treatment for even profound loss as long as someone can get something in pre-clinical in the next 5 years and she said plenty of people are working on this (she said AAV treatments designed specifically to work on the flat epithelial would be the eventual thing that might help me and others). This is why I have been uncertain of my future on this Earth lately. I really don't think I personally without a family especially can wait 15-20 years BUT I am no less confident all of you with less severe losses, esp the noise induced folks will be fine in a much more reasonable time frame.

With your case specifically, "almost no hearing" is not necessarily profound hearing loss. Profound loss has an audiometric cut off and is over 90dB, though for the lowest frequencies it can be hard to accurately test for (because of this, even a 40db-50db loss at the apex indicates a "cochlear dead zone" because the signal moves upward and is still perceived though not at the right tone...i just learned about this recently). I would get an extended audiogram if you haven't already.

 

[Danad]

Yes, very new and extremely promising.

It's a surgical procedure to get to the edge of the semi circular canal where the injection is given. I'm not sure if it has yet been tried on humans but Chen has mentioned using that approach for his drugs in one of his papers. It's apparently a technically "easier" surgery with much less risk than the cochleastomy that's already done. I haven't seen any paper mention any anatomic difference that would prevent this in humans. The fact that hearing regeneration researchers are looking into this (there has been an uptick in papers on this) tells me it's being seriously looked into.

If you truly have profound hearing loss you will eventually get "flat epithelial" in that location which is devoid of all IHC, OHC and SCs. I spoke to a "flat epithelial/profound hearing loss" researcher and this what she said:

"Profound hearing loss in an audiogram suggests that you have no sensory HCs or supporting cells or auditory nerves in these regions."

She said many studies, including her own have confirmed this. She did feel optimistic, though, that in 15-20 years there would be a treatment for even profound loss as long as someone can get something in pre-clinical in the next 5 years and she said plenty of people are working on this (she said AAV treatments designed specifically to work on the flat epithelial would be the eventual thing that might help me and others). This is why I have been uncertain of my future on this Earth lately. I really don't think I personally without a family especially can wait 15-20 years BUT I am no less confident all of you with less severe losses, esp the noise induced folks will be fine in a much more reasonable time frame.

With your case specifically, "almost no hearing" is not necessarily profound hearing loss. Profound loss has an audiometric cut off and is over 90dB, though for the lowest frequencies it can be hard to accurately test for (because of this, even a 40db-50db loss at the apex indicates a "cochlear dead zone" because the signal moves upward and is still perceived though not at the right tone...i just learned about this recently). I would get an extended audiogram if you haven't already.

I think it is important to recognize some possibilities with FX-322 and its probable impact on tinnitus.

It is likely that the diffusion with multiple dosages will, with increases in time and concentration, reach to lower frequencies. It is also likely that there are a few progenitor cells remaining which are first doubled prior to a twin converting to a IHC/OHC thereby not depleting any LGR5s. Essentially allowing for many future treatments. Even a slight signal gain may be enough to subdue the manifestation of tinnitus. We do know that hearing restoration tames tinnitus, but not to what degree with threshold shifts upward.

 

[FGG]

I think it is important to recognize some possibilities with FX-322 and its probable impact on tinnitus.

It is likely that the diffusion with multiple dosages will, with increases in time and concentration, reach to lower frequencies. It is also likely that there are a few progenitor cells remaining which are first doubled prior to a twin converting to a IHC/OHC thereby not depleting any LGR5s. Essentially allowing for many future treatments. Even a slight signal gain may be enough to subdue the manifestation of tinnitus. We do know that hearing restoration tames tinnitus, but not to what degree with threshold shifts upward.

Oh I agree. Eventually Frequency will do this but it might take a year or two after FX-322 comes out. Hanging around the suicide thread long enough, I have come to realize that for some people though it can be a matter of life or death.

 

[dan]

BUT I am no less confident all of you with less severe losses, esp the noise induced folks will be fine in a much more reasonable time frame.

I have 100% noise induced tinnitus and I have like 40-50 dB loss at 8 kHz. It was caused by a fire alarm.

Audiogram looks like a sloping down type.
I hear tv on low volume fine and I don't notice any defects in listening music.
My highest tinnitus frequency is around 8 kHz and I have a couple others at other frequencies and sounds below that.

So FX-322 is not for me either?

Why do you think drug induced and noise induced hearing loss are different?
Hearing loss is hearing loss regardless how it happened, no???

Also, if I have support cells up to, say 10kHz for example. So FX-322 restores my hearing up to that (losses 10 dB up to 30 dB), since my tinnitus noises are all below 10 kHz (and I have a shitload of sounds at this point), shouldn't my tinnitus vastly improve?

 

[AtlasFainted]

Yes, very new and extremely promising.

It's a surgical procedure to get to the edge of the semi circular canal where the injection is given. I'm not sure if it has yet been tried on humans but Chen has mentioned using that approach for his drugs in one of his papers. It's apparently a technically "easier" surgery with much less risk than the cochleastomy that's already done. I haven't seen any paper mention any anatomic difference that would prevent this in humans. The fact that hearing regeneration researchers are looking into this (there has been an uptick in papers on this) tells me it's being seriously looked into.

If you truly have profound hearing loss you will eventually get "flat epithelial" in that location which is devoid of all IHC, OHC and SCs. I spoke to a "flat epithelial/profound hearing loss" researcher and this what she said:

"Profound hearing loss in an audiogram suggests that you have no sensory HCs or supporting cells or auditory nerves in these regions."

She said many studies, including her own have confirmed this. She did feel optimistic, though, that in 15-20 years there would be a treatment for even profound loss as long as someone can get something in pre-clinical in the next 5 years and she said plenty of people are working on this (she said AAV treatments designed specifically to work on the flat epithelial would be the eventual thing that might help me and others). This is why I have been uncertain of my future on this Earth lately. I really don't think I personally without a family especially can wait 15-20 years BUT I am no less confident all of you with less severe losses, esp the noise induced folks will be fine in a much more reasonable time frame.

With your case specifically, "almost no hearing" is not necessarily profound hearing loss. Profound loss has an audiometric cut off and is over 90dB, though for the lowest frequencies it can be hard to accurately test for (because of this, even a 40db-50db loss at the apex indicates a "cochlear dead zone" because the signal moves upward and is still perceived though not at the right tone...i just learned about this recently). I would get an extended audiogram if you haven't already.

Thanks so much! I will look into getting an extended audiogram.

With tests I found online, my hearing in my right ear seems to drop off entirely at around 9kHz and comes back quietly between 11kHz-13kHz before dropping off again.

How long does it take for the support cells/nerves to die off completely? This whole time I thought that most of us have complete loss at certain high frequencies and that's why we have tinnitus... I wasn't aware that the majority of us only have volume reduction in the high frequencies.

I'm feeling pretty sad/worried right now in light of this news. My right ear seems deaf for the majority of frequencies 9kHz+. I can play a 12kHz tone on my phone and not hear anything at all on my right ear, until moving it to my left ear where I percieve it fine. Does this mean FX-322 might not help me?

Shit...

 

[FGG]

I have 100% noise induced tinnitus and I have like 40-50 dB loss at 8 kHz. It was caused by a fire alarm.

Audiogram looks like a sloping down type.
I hear tv on low volume fine and I don't notice any defects in listening music.
My highest tinnitus frequency is around 8 kHz and I have a couple others at other frequencies and sounds below that.

So FX-322 is not for me either?

Why do you think drug induced and noise induced hearing loss are different?
Hearing loss is hearing loss regardless how it happened, no???

Also, if I have support cells up to, say 10kHz for example. So FX-322 restores my hearing up to that (losses 10 dB up to 30 dB), since my tinnitus noises are all below 10 kHz (and I have a shitload of sounds at this point), shouldn't my tinnitus vastly improve?

50 dB is well within the range Frequency plans to address. Drugs are probably case by case. I worry most about Macrolides and Cisplatin/Carboplatin.

 

[FGG]

Thanks so much! I will look into getting an extended audiogram.

With tests I found online, my hearing in my right ear seems to drop off entirely at around 9kHz and comes back quietly between 11kHz-13kHz before dropping off again.

How long does it take for the support cells/nerves to die off completely? This whole time I thought that most of us have complete loss at certain high frequencies and that's why we have tinnitus... I wasn't aware that the majority of us only have volume reduction in the high frequencies.

I'm feeling pretty sad/worried right now in light of this news. My right ear seems deaf for the majority of frequencies 9kHz+. I can play a 12kHz tone on my phone and not hear anything at all on my right ear, until moving it to my left ear where I percieve it fine. Does this mean FX-322 might not help me?

Shit...

You don't have to have profound hearing loss to not hear it with your phone. That's why you need an audiogram. Support cells don't automatically die en masse, either. It takes losing all of your OHCs and IHCs first (i.e. profound loss) for that to happen. Most people never get to profound.

 

[Diesel]

I'm feeling pretty sad/worried right now in light of this news. My right ear seems deaf for the majority of frequencies 9kHz+. I can play a 12kHz tone on my phone and not hear anything at all on my right ear, until moving it to my left ear where I percieve it fine. Does this mean FX-322 might not help me?

Shit...

No one here knows for sure. All we can do is speculate whether FX-322 will reduce tinnitus symptoms.

I think right now many are trying to base any speculation on the effectiveness of FX-322 on studies/research based on old paradigms of our understanding of hearing loss. Much of it is pretty dismal. Regeneration will change that thinking.

Personally, I believe FX-322 hasn't made tinnitus worse for any study participant. We would know by now. It would be a safety issue.

If one were to assume tinnitus as a symptom of missing or damaged hair cells, than it seems obvious that the regrowth would lessen or eliminate the symptom.

If we come to find out that tinnitus is lessened for participants of the phase 2a, even if by 20%... that's a huge win for many.

 

[all to gain]

Thanks so much! I will look into getting an extended audiogram.

With tests I found online, my hearing in my right ear seems to drop off entirely at around 9kHz and comes back quietly between 11kHz-13kHz before dropping off again.

How long does it take for the support cells/nerves to die off completely? This whole time I thought that most of us have complete loss at certain high frequencies and that's why we have tinnitus... I wasn't aware that the majority of us only have volume reduction in the high frequencies.

I'm feeling pretty sad/worried right now in light of this news. My right ear seems deaf for the majority of frequencies 9kHz+. I can play a 12kHz tone on my phone and not hear anything at all on my right ear, until moving it to my left ear where I percieve it fine. Does this mean FX-322 might not help me?

Shit...

This is basically the same question I asked a page or two back. It is worrying to say the least. This for me makes it even more vital that they get FX-322 on the market as soon as possible.

I would love to get an extended audiogram, but they do not offer them here at all.

 

[Croaker]

Thanks so much! I will look into getting an extended audiogram.

With tests I found online, my hearing in my right ear seems to drop off entirely at around 9kHz and comes back quietly between 11kHz-13kHz before dropping off again.

How long does it take for the support cells/nerves to die off completely? This whole time I thought that most of us have complete loss at certain high frequencies and that's why we have tinnitus... I wasn't aware that the majority of us only have volume reduction in the high frequencies.

I'm feeling pretty sad/worried right now in light of this news. My right ear seems deaf for the majority of frequencies 9kHz+. I can play a 12kHz tone on my phone and not hear anything at all on my right ear, until moving it to my left ear where I percieve it fine. Does this mean FX-322 might not help me?

Shit...

I seriously doubt it would have zero effect for you. It's way too early to give up, but I know that us sufferers can't help but speculate. We'll know 100x more with the phase 2 results.

 

[Utopia]

BUT I am no less confident all of you with less severe losses, esp the noise induced folks will be fine in a much more reasonable time frame.

Curious... How long do you estimate this reasonable time frame to be and why? I consider you to have breadth and depth of regeneration research knowledge. Thank you!

You are much too valuable to us and this world to depart. You are gifted... and I hope a reason for you to wait it out with us manifests.

 

[xyz]

Stem cells can transform into all kinds of cells but progenitor cells are not that 'flexible' so they transform into more 'fixed' types.

When these progenitor cells are destined to become hair cells with FX-322 then this seems to be a much safer approach than the stem cell treatment as there you always run into the risk of cancer development.

Why do you think drug induced and noise induced hearing loss are different?
Hearing loss is hearing loss regardless how it happened, no???

Probably a drug can be toxic to any parts of the body. So i.e. the auditory nerve. But FX-322 regenerates hair cells, not the auditory nerve.

 

[AtlasFainted]

You don't have to have profound hearing loss to not hear it with your phone. That's why you need an audiogram. Support cells don't automatically die en masse, either. It takes losing all of your OHCs and IHCs first (i.e. profound loss) for that to happen. Most people never get to profound.

Thanks for this. I hold your opinion in very high esteem and this gave me comfort. I'll schedule an extended audiogram.

 

[sssing]

You don't have to have profound hearing loss to not hear it with your phone. That's why you need an audiogram. Support cells don't automatically die en masse, either. It takes losing all of your OHCs and IHCs first (i.e. profound loss) for that to happen. Most people never get to profound.

Sorry I know you know much about this so I really would like your opinion on this, but from what I understand to be really sure that you only have flat epithelia left you need profound losses in all or a lot of frequencies on your audiogram?

 

[sssing]

Curious... How long do you estimate this reasonable time frame to be and why? I consider you to have breadth and depth of regeneration research knowledge. Thank you!

You are much too valuable to us and this world to depart. You are gifted... and I hope a reason for you to wait it out with us manifests.

Yes I agree, @FGG you are really doing good here in BIG ways.

 

[ThomasC]

Here is my extended audiogram. I 'm afraid that FX-322 may not fully work. I guess that the cochlear zone around 11kHz is dead.

 

[FGG]

This is basically the same question I asked a page or two back. It is worrying to say the least. This for me makes it even more vital that they get FX-322 on the market as soon as possible.

I would love to get an extended audiogram, but they do not offer them here at all.

Sometimes cancer centers offer them because they can be used to monitor the early effects of Cisplatin. Research universities are another place to try.